Published online 10 November 2017 Nucleic Acids Research, 2018, Vol. 46, Database issue D661–D667 doi: 10.1093/nar/gkx1064 WikiPathways: a multifaceted pathway database bridging metabolomics to other omics research Denise N. Slenter1, Martina Kutmon1,2, Kristina Hanspers3, Anders Riutta3, Jacob Windsor1, Nuno Nunes1, Jonathan Melius´ 1, Elisa Cirillo1, Susan L. Coort1, Daniela Digles4, Friederike Ehrhart1, Pieter Giesbertz5, Marianthi Kalafati1,2, Marvin Martens1, Ryan Miller1, Kozo Nishida6, Linda Rieswijk7, Andra Waagmeester1,8, Lars M.T. Eijssen1,9, Chris T. Evelo1,2, Alexander R. Pico3 and Egon L. Willighagen1,*

1Department of Bioinformatics - BiGCaT, NUTRIM, Maastricht University, 6229 ER Maastricht, The Netherlands, 2Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, 6229 ER Maastricht, The Netherlands, 3Gladstone Institutes, San Francisco, California, CA 94158, USA, 4University of Vienna, Department of Pharmaceutical Chemistry, 1090 Vienna, Austria, 5Chair of Nutritional Physiology, Technische Universitat¨ Munchen,¨ 85350 Freising, Germany, 6Laboratory for Biochemical Simulation, RIKEN Quantitative Biology Center, Suita, Osaka 565-0874, Japan, 7Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720, USA, 8Micelio, Antwerp, Belgium and 9School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands

Received September 14, 2017; Revised October 09, 2017; Editorial Decision October 10, 2017; Accepted October 25, 2017

ABSTRACT omics data. New search options, monthly downloads, more links to metabolite databases, and new portals WikiPathways (.org) captures the col- make pathway knowledge more effortlessly accessi- lective knowledge represented in biological path- ble to individual researchers and research communi- ways. By providing a database in a curated, ma- ties. chine readable way, omics data analysis and visu- alization is enabled. WikiPathways and other path- way databases are used to analyze experimental data INTRODUCTION by research groups in many fields. Due to the open and collaborative nature of the WikiPathways plat- The WikiPathways initiative (wikipathways.org)startedin 2008, creating a platform where pathway curation could form, our content keeps growing and is getting more be performed by means of crowd sourcing (1). The plat- accurate, making WikiPathways a reliable and rich form’s knowledge-base supports many life sciences com- pathway database. Previously, however, the focus munities, ranging from biology (2) to drug discov- was primarily on and , leaving many ery (3). The use of pathway knowledge in the life sciences metabolites with only limited annotation. Recent cu- is wide-spread, supported by many databases (4–6)aswell ration efforts focused on improving the annotation of as integrative resources (7,8). WikiPathways has been used and metabolic pathways by associating to analyze and integrate experimental transcriptomics, pro- unmapped metabolites with database identifiers and teomics, and metabolomics data (9–12). Our previous up- providing more detailed interaction knowledge. Here, date reported over 2300 pathways for 25 different we report the outcomes of the continued growth and (13) and over the last two years this number has increased curation efforts, such as a doubling of the number by 14% to 2614 pathways, as of September 2017. Through pathway curation and the addition of new pathways, of annotated metabolite nodes in WikiPathways. Fur- coverage present in at least one of our pathways has thermore, we introduce an OpenAPI documentation increased from 30% (7600) to ∼50% (11 532) of all unique of our web services and the FAIR (Findable, Acces- human -coding genes, see Figure 1. sible, Interoperable and Reusable) annotation of re- The WikiPathways database is improved by continuous sources to increase the interoperability of the knowl- data curation and updates through an expanding commu- edge encoded in these pathways and experimental nity: 634 individual contributors to date and 2850 edits on 1060 pathways between August 2016 to August 2017. The

*To whom correspondence should be addressed. Tel: +31 43 3881231; Fax: +31 43 3881999; Email: [email protected]

C The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. D662 Nucleic Acids Research, 2018, Vol. 46, Database issue

Figure 1. Overview of coverage of various gene spaces. WikiPathways (WP) currently covers 11 532 unique human genes. Venn diagram A shows that 50% of the protein coding genes (Ensembl: 22 376 genes) are found in WikiPathways. B shows the 66% coverage of all disease genes (OMIM: 15,262 genes), which also illustrates that the vast majority of genes in WikiPathways are associated with a disease. The C diagram shows that WikiPathways covers 71% of all genes known to be involved in human metabolism (GO metabolic process: 11 296 genes). availability of all data under a liberal license (wikipathways. org/license) ensures that all contributors benefit from the collective effort of the full WikiPathways community. Sim- ilar to the pathway data, the code base is open source and associated formats and ontologies conform to open stan- dards, allowing other developers to participate and join the team (github.com/wikipathways). Pathways are encoded in GPML format and created with PathVisio (14). Genes, pro- teins and metabolites are linked to other databases with the BridgeDb web service (15). All components are freely avail- able, developed in open collaborations and distributed as open source or open access products. This paper describes our efforts to increase the knowledge covered by biological pathways, with a focus on metabolites, and the usability of WikiPathways in general. These efforts include a more accurate annotation of chemical identities of metabolites, their enzymatic conversions, and protein in- teractions. This work was triggered by the coming of age of the metabolomics field16 ( ), resulting in a growing amount of experimental data (17). The following sections describe our work of the past two years, organized as updates for biologists and chemists, updates for contributors and cura- tors, and updates for bioinformaticians and data scientists. Figure 2. Metabolite coverage growth in WikiPathways. Taking KEGG as the standard, we plot the growth of WikiPathways (WP) coverage over UPDATES FOR BIOLOGISTS AND CHEMISTS the past five years. WikiPathways and KEGG unique human metabolite counts were calculated by extracting identifiers from archived WikiPath- To quantify the results of our curation efforts regarding the ways releases and unifying to, ideally, Wikidata ID, otherwise ChEBI or growth in metabolite data, the numbers of annotated hu- HMDB. About two-third of all identifiers (blue line) could be mapped to man metabolites over the past years are shown in Figure a Wikidata (red line). Metabolite IDs that could not be mapped to these three databases, have decreased over the last five years (unmapped, green 2. Comparing the last five years, the total number of an- line). notated unique metabolite nodes follow a positive trend, having grown by 158% from 1213 in 2013 to 3133 in 2017. The total number of unique metabolites was estimated by Biochemical Pathways map (Giesbertz, P., Willighagen, E. counting the unique number of identifiers: all metabolite and Slenter, D. (2017) Biochemical Pathways Part I (Homo annotations were first normalized to Wikidata identifiers sapiens). wikipathways.org/instance/WP3604 r94542). Re- (18), second to ChEBI (19),thirdtoHMDB(20), in that actome pathways have been updated to version 61 us- order, when the normalization to Wikidata was not possi- ing an extended version of the previously reported Re- ble. If none of these three databases provided an identifier actome2GPML converter (21). This converter adds com- for the listed compound, we refer to the metabolite iden- ments to pathway descriptions stating the original Reac- tifier as unmapped. Importantly, the percentage of human tome pathway ID, version, and author list. metabolites without annotation for the full set of pathways Additionally, a considerable contribution to the growth decreased from 5% to 1% over the last five years. comprises improved annotation and curation efforts. We Last year’s growth can partly be explained by the addi- improved the biological annotation of several small car- tion of large metabolic pathways as new content, such as the bohydrates for multiple Homo sapiens pathways, such Nucleic Acids Research, 2018, Vol. 46, Database issue D663 as the Glycolysis and Gluconeogenesis pathway (User- any published pathway figure to be digitized and made ma- name:Kdahlquist, Coort, S., Fidelman, N., van Iersel, M., chine readable. We will prioritize requested pathways and Hanspers, K., Kelder, T., Bouwman, J., Pico, A., Wil- assign pathway modeling tasks to people in our curation lighagen, E., Kutmon, M., et al. (2017) Glycolysis and team. Given that thousands of pathway images are avail- Gluconeogenesis (H. sapiens). wikipathways.org/instance/ able, such prioritization is needed (26). Second, users can of- WP534 r94762). We now discriminate between the straight- fer their general feedback in our WikiPathways User Survey chain (open) and cyclic (closed) forms of glucose-6- (surveymonkey.com/r/wikipathways). We use the responses phosphate and fructose-6-phosphate and their conversions to gauge how WikiPathways is used in research in order to into one another. We hope that this and future work on prioritize new feature development. carbohydrates in our pathways will result in a better visu- alization of data from the glycomics field. In order to let Future plans WikiPathways tell the full biological story of a pathway, all elements need to be specified as a gene, protein, metabolite, Ongoing projects extend WikiPathways to support the or pathway node, and associated with an identifier. Further needs of biologists and chemists. For example, we are curation work was aimed at improving the annotation of in the process of explicitly organizing a complete path- pathways, e.g. by annotating interactions in pathways with way archive based on ontology tags. These ontologies are their directionality information, such as the direction of en- sourced from the comprehensive collection of biomedical zymatic reactions and the involved enzyme(s). Part of the ontologies available at BioPortal (27). Future search and growth, therefore, is due to converting metabolites repre- browse features will use ontologies to enable users to find sented as text labels to metabolite nodes. Figure 3 shows relevant pathways. Another project works on a tool to repre- the effect of such curation on a pathway. sent pathway information regarding molecular classes and states for Cytoscape (28). First, the tool will describe the targets of microRNA in pathways, which is currently given Links to other databases in 109 WikiPathways, with 1067 occurrences (across all In order to link other databases and to map experimental species). Second, an information class named protein mod- data onto pathways, it is crucial to annotated WikiPath- ifications is added in pathways. Several pathways include ways nodes with identifiers. BridgeDb is the identifier map- protein nodes with state information, such as phosphoryla- ping tool used to translate identifiers in pathways to those in tion (1852 occurrences in 119 pathways) and ubiquitination experimental data sets and third party databases (15). The (47 occurrences in 26 pathways, across all species) states. pathways use various databases for annotation of metabo- The WikiPathways app for Cytoscape will use this machine lites, e.g. ChEBI and HMDB. In this new release, we added readable annotation to support data visualization on pro- links to additional databases, e.g. KNApSAcK (22,23), tein states in the next release, scheduled to coincide with LIPID Maps (24), and the EPA CompTox Dashboard (25). Cytoscape 3.6.0 (28). The Pathway Finder tool will be ex- The mappings for these new databases are stored in and de- panded to include transcription factor targets and drug tar- rived from Wikidata and ChEBI. For the EPA CompTox gets searches in the near future. Dashboard alone, 36 thousand identifier mappings have been added to Wikidata to support this new link out in UPDATES FOR PATHWAY AUTHORS AND CURA- WikiPathways, using mapping data provided by the EPA TORS (doi.org/10.6084/m9.figshare.3578313.v1). WikiPathways Academy To support the authoring of new pathways, we created a Pathway Finder tool new interactive training environment called WikiPathways Besides updated content, biologists and chemists will also Academy (academy.wikipathways.org), which aims to pro- benefit from updates to the WikiPathways website it- vide comprehensive and easy-to-use training. The Academy self. For example, a new search tool is available called covers all aspects of pathway authoring, from basic con- Pathway Finder (wikipathways.org/pathway-finder/demo), cepts and terminology to various authoring tools. Designed which can be used to find pathways based on indirect as a step-wise path (academy.wikipathways.org/path.html), queries, such as targets of specific microRNAs or which the Academy starts with a ‘Biology 101’ primer on path- metabolites are converted by specific enzymes. way concepts, followed by a ‘Walk along a pathway’, in- troducing the user to reading and interpreting pathways, and then using ‘Pathway Building Blocks’ to finally build Feedback and requests ‘My First ’. Authors are also trained on Feedback and requests from the WikiPathways commu- how to leverage the WikiPathways website to create an ac- nity are important to us. To facilitate more interac- count, publish pathways and complete pathways with on- tion between the developers, curators, authors, and users, tology categories, descriptions and more. on generic and specific questions about the WikiPath- WikiPathways Academy is designed to give the user im- ways project, tools, and pathways, we have complemented mediate feedback on training tasks, thus creating a more ef- our discussion group (groups.google.com/forum/#!forum/ fective training experience. Each step in the path consists of wikipathways-discuss) with new communication channels. multiple choice questions, pathway editing challenges, and First, we implemented an updated request form (goo.gl/ WikiPathways website tasks. For editing tasks, a pathway forms/FE6Ab347OLa7cBzr1), where anyone can suggest editor is launched directly from each challenge, and results D664 Nucleic Acids Research, 2018, Vol. 46, Database issue

Figure 3. Previous and updated Glucose-1-phosphate metabolism (Saccharomyces cerevisiae) pathway diagram: the original pathway (left, Heckman, J., Chichester, C. and Willighagen, E. (2016) Glucose-1-phosphate metabolism (Saccharomyces cerevisiae). wikipathways.org/instance/WP260 r89691)rep- resented the reactions as five separate chemical reactions and with several metabolites as text labels. After curation, the improved pathway (right, Heck- man, J., Chichester, C., Willighagen, E., Slenter, D. and Kutmon, M. (2017) Glucose-1-phosphate metabolism (S. cerevisiae). wikipathways.org/instance/ WP260 r94487) shows connected reactions with annotated metabolites. are verified automatically by a simple drag-and-drop inter- Computer-aided curation with Jenkins face. For the WikiPathways website tasks, the author per- The curators are further supported by automated testing. forms actions at WikiPathways.org and the Academy auto- A test suite is run by a build service using the Jenkins matically verifies each change. software (jenkins.io) and uses the WikiPathways RDF that is generated from the GPML twice every day (29). The Quality Assurance protocol update suite includes more than sixty tests using a combination Taking advantage of the new training platform, we have re- of SPARQL queries and Java code to test for a variety designed our Quality Assurance (QA) protocol as an in- of recurrent issues. For example, one class of tests detects teractive experience at WikiPathways Academy, (academy. the use of old data source names, such as Kegg Compound wikipathways.org/qaprotocol). The protocol consists of and PubChem where people should now use KEGG Com- seven basic and five optional tasks, covering screening of pound, PubChem-compound or PubChem-substance.Other new pathways and recent edits, orienting new users, fix- tests check identifiers for unexpected values, such as non- ing poorly annotated pathways and nodes, and evaluating numerical PubMed identifiers or non-numerical identifiers the content of pathway collections for downstream analy- for Entrez Gene and PubChem-compound. Some tests also sis. Within each task, the curator is presented with relevant include more specific interpretation of the data. For ex- pathways one-by-one in a built-in pathway viewer, from ample, tests that ensure that genes are not annotated with which they can seamlessly open the pathway at WikiPath- metabolite identifiers, or that gene-gene interactions do not ways to make necessary changes. Each task contains a de- represent a gene conversion. Curators can inspect the test tailed description of the curation steps involved, in order to results at their convenience at (jenkins.bigcat.unimaas.nl), assure a consistent workflow. The QA protocol is open to while this system also informs curators if a failure is de- anyone interested in improving pathway content. We also tected via a push message. continuously recruit a dedicated team of curators, whom ro- tate on a weekly basis and are displayed as the ‘Curator of the Week’ on the front page of the WikiPathways website. Nucleic Acids Research, 2018, Vol. 46, Database issue D665

New portals org), which is available at webservice.wikipathways.org. Matching client side libraries for Java, JavaScript, Python, New portals have been set up to support specific com- and R have been updated and are available at (github. munities. A new collaboration started with scientists from com/wikipathways/) under wikipathways-api-client-java, the Garvin lab at Case Western Reserve (physiology.case. wikipathways-api-client-js, wikipathways-api-client-py and edu/research/labs/garvin-lab) to develop resources for re- rwikipathways. With the use of OpenAPI tools, client code nal genomics research. As a first step, we created a new can be automatically generated for other popular program- Renal Genomics portal at WikiPathways (renalgenomics. ming languages, if needed. wikipathways.org), which showcases 11 pathways. This ef- Noteworthy is the recent license change of the WikiPath- fort aims to produce high-quality pathways with tissue/cell- ways content. After community requests to include pathway specificity for kidney disease and biology, and to attract re- content in Wikidata, and consultation with the author com- searchers in this domain to collaborate on pathway mod- munity, the CC-BY license was replaced by the more liberal eling. As part of an ongoing collaboration, a portal was CCZero waiver. With this waiver, WikiPathways is placed as created for pathway content relevant to the National Can- completely as possible in the public domain, so that others cer Institute’s Clinical Proteomic Tumor Analysis Consor- may freely build upon, enhance and reuse our works for any tium (CPTAC, cptac.wikipathways.org). CPTAC aims to purposes without restriction under copyright or database accelerate the understanding of the molecular basis of can- law. This change enables inclusion in Wikidata and bene- cer through the application of large-scale proteome and fits other projects that reuse the pathways. The availability genome analysis. Pathways in the portal are annotated with of the human WikiPathways in Wikidata allows enriching post-translational modifications at the protein level (states), these pathways with the other biomedical data (30), and such as phosphorylation, methylation and ubiquitination, a few example queries available at (wikidata.org/wiki/User: to facilitate data overlay and integration with other CPTAC Pathwaybot/query examples) demonstrate the advantages. tools.

Issue tracker Future plans In addition to the aforementioned feedback mechanisms, First, a new tool, named Pathway Presenter developers are further supported by the ability to request (pathwaypresenter.jcbwndsr.com), has been developed new features and provide feedback regarding WikiPathways to create visual presentations of the pathway diagrams via the issue tracker on GitHub (github.com/wikipathways/ from WikiPathways. With this tool, presentation slides can wikipathways.org/issues). be created where nodes in the pathway are for example highlighted or hidden. This tool will soon be released as an integrated presentation builder and viewer launched Reusability of WikiPathways database from any pathway page at WikiPathways.org. Second, To further automate dissemination, we adopted the recently a recent analysis showed that 150 pathways have been introduced FAIR principles, which propose to enhance the cited in literature by their pathway identifier. We want to Findability, Accessibility, Interoperability, and Reusability provide different citation styles, compatible with programs of metadata (31). To achieve this goal a FAIR data point that make use of e.g. BibTeX and Endnote, for individual (FDP)wassetupat(fdp.wikipathways.org). The FDP im- pathways. By adoption of data citation standards, we plements the FAIR principles by the use of rich metadata want to enable researchers to effortlessly and accurately and resource description, using linked data approaches and acknowledge pathway authors. public ontologies. The FDP describes the data resources, provides clear copyright and license information, prove- UPDATES FOR DATA MINERS AND PROGRAMMERS nance information about when the data was generated and by whom, and points to a download location. This infor- Data availability mation allows search engine crawlers to find and index the We initiated a new archive for monthly releases of resources, implementing the findability requirement of the WikiPathways content at (data.wikipathways.org). Each re- FAIR principles. lease includes the updated contributed pathway content that has undergone community curation and internal qual- Future plans ity assurance to ensure (i) standard identifiers for genes, pro- teins and metabolites, (ii) properly modeled interaction and A development regarding semantic web formats is a project reactions, (iii) adequate descriptions and tags, (iv) litera- to create nanopublications of facts captured in WikiPath- ture references and (v) ontology term annotations. These re- ways, such as which biological entities are interacting leases currently provide the pathway content in formats for with each other. Nanopublications have a rich provenance computational analysis (GPML, GMT, RDF) and for vi- model, allowing stating the origin of the fact, linking to spe- sualization (SVG). Daily releases and other formats (PNG, cific research papers, or even to experiments32 ( ,33). PDF or BioPAX) are also available from the main down- load page (wikipathways.org/download). CONCLUSION Web services are available for programmatic access to WikiPathways content. We also now provide interactive The WikiPathways project is thriving. The FAIR and open Swagger documentation using OpenAPI (www.openapis. science approach and the extensive community support D666 Nucleic Acids Research, 2018, Vol. 46, Database issue

continues to trigger growth of the project and the database 9. Jennen,D.G., Gaj,S., Giesbertz,P.J., van Delft,J.H., Evelo,C.T. and content. In the following years, our growth will be sup- Kleinjans,J.C. (2010) Biotransformation pathway maps in ported by recently renewed funding. The updates presented WikiPathways enable direct visualization of drug metabolism related expression changes. Drug Discov. Today, 15, 851–858. here, for biologist, chemists, authors, curators, and data sci- 10. Mastrokolias,A., Pool,R., Mina,E., Hettne,K., van Duijn,E., van der entists, demonstrate the success of our approach and open Mast,R., van Ommen,G., ’t Hoen,P., Prehn,C., Adamski,J. et al. up new ways in which biological complexity can be repre- (2016) Integration of targeted metabolomics and transcriptomics sented and reused by others. Examples of such complexity identifies deregulation of phosphatidylcholine metabolism in Huntington’s disease peripheral blood samples. Metabolomics, 12, include post-translational modifications affecting protein 137. activity and the temporal dynamics of processes. Our recent 11. Kohonen,P., Parkkinen,J.A., Willighagen,E.L., Ceder,R., efforts around the content and curation of metabolic path- Wennerberg,K., Kaski,S. and Grafstrom,R.C.¨ (2017) A ways show a high potential for adoption by the metabolism transcriptomics data-driven gene space accurately predicts liver and metabolomics communities and those applying these cytopathology and drug-induced liver injury. Nat. Commun., 8, 15932. technologies. In fact, the demonstrated continued growth 12. Azad,A., Lawen,A. and Keith,J.M. (2017) Bayesian model of signal in content and features since the 2016 update shows we are rewiring reveals mechanisms of gene dysregulation in acquired drug getting closer to reaching our commitment to capture every resistance in breast cancer. PLoS ONE, 12, e0173331. pathway of interest and share them in as many useful ways 13. Kutmon,M., Riutta,A., Nunes,N., Hanspers,K., Willighagen,E.L., Bohler,A., Melius,J.,´ Waagmeester,A., Sinha,S.R., Miller,R. et al. as possible. (2016) WikiPathways: capturing the full diversity of pathway knowledge. Nucleic Acids Res., 44, D488–D494. 14. Kutmon,M., van Iersel,M.P., Bohler,A., Kelder,T., Nunes,N., ACKNOWLEDGEMENTS Pico,A.R. and Evelo,C.T. (2015) PathVisio 3: an extendable toolbox. PLoS Comput. Biol., 11, e1004085. Thanks to all the people who contributed to WikiPathways 15. van Iersel,M.P., Pico,A.R., Kelder,T., Gao,J., Ho,I., Hanspers,K., content, code and discussions and who used the content of Conklin,B.R. and Evelo,C.T. (2010) The BridgeDb framework: WikiPathways in their projects. standardized access to gene, protein and metabolite identifier mapping services. BMC Bioinf., 11,5. 16. Kell,D.B. and Oliver,S.G. (2016) The metabolome 18 years on: a FUNDING concept comes of age. Metabolomics, 12, 148. 17. 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